Evaluation of Prolonged Anticoagulation with Enoxaparin and Apixaban for Venous Thromboembolism Prevention in Autoimmune Hemolytic Anemia Patients

Trial ID: 2024-513191-17-00
Sponsor: Centre Hospitalier Universitaire De Dijon

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Diseases & Conditions

Autoimmune haemolytic anaemia

Objectives

The primary objective of this study is to evaluate the **efficacy** of prolonged prophylactic anticoagulation in patients with warm-type autoantibody autoimmune hemolytic anemia (AIHA) at diagnosis or relapse. The study aims to assess the impact of a 12-week anticoagulation regimen, starting with heparin therapy (enoxaparin 4000 IU/day subcutaneously) during hospitalization, followed by oral anticoagulation with apixaban (2.5 mg morning and evening), on the occurrence of venous thromboembolism (VTE) at 24 weeks. This is clinically relevant as it addresses the prevention of VTE, a significant complication in patients with AIHA, potentially improving patient outcomes and reducing morbidity.

Secondary objectives include:

Describing the time to onset of thromboembolic events.
Studying the tolerability of apixaban in prophylactic doses.
Describing biological markers of thromboembolic risk in AIHA.
Exploratory: comparing VTE frequency and time to onset between intervention and standard arms.

These objectives aim to provide a comprehensive understanding of the treatment's impact on thromboembolic events, patient safety, and potential biomarkers, which could inform future therapeutic strategies and risk assessment in AIHA.

Participants

The clinical trial involves participants diagnosed with **autoimmune hemolytic anemia** (AIHA), specifically focusing on those with warm-type autoantibody AIHA at diagnosis or relapse. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a hemoglobin level of less than 12 g/dL, decreased haptoglobin levels, and a positive direct antiglobulin test. The trial does not include a vulnerable population. Participants must have an estimated life expectancy of more than six months. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that individuals are newly diagnosed or experiencing a relapse, necessitating specific etiological treatment for AIHA. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of prolonged prophylactic anticoagulation in patients with **autoimmune hemolytic anemia** (AIHA). The trial involves the administration of **enoxaparin sodium** via subcutaneous injection during hospitalization, followed by oral administration of **apixaban**. The primary objective is to assess the occurrence of venous thromboembolic events within 24 weeks. The study is expected to last until August 2028, with participant recruitment having commenced in February 2022.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age, diagnosis of AIHA, and life expectancy. The inclusion visit will involve screening procedures to ensure compliance with the principal inclusion criteria, including hemoglobin levels and direct antiglobulin test results. Following randomization, participants will receive treatment for a maximum of 12 weeks, with enoxaparin administered for up to 4 weeks and apixaban for the remaining period.

Follow-up visits will be scheduled to monitor the occurrence of venous thromboembolic events and adverse events, including major and non-major bleeding. These visits will also assess the time to onset of thromboembolic events and any major cardiovascular events. The end-of-study visit will occur at the 24-week mark to evaluate the primary and secondary endpoints, including the determination of biological factors related to thromboembolic risk.

Participant involvement is expected to last approximately 24 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and adherence to ethical standards.

Treatment

The clinical trial involves the administration of **ENOXAPARIN SODIUM**, a low molecular weight heparin, as part of the experimental treatment regimen. This medication is provided in the form of a **solution for injection** and is administered via **subcutaneous injection**. The dosage is set at 4000 IU per day, with a maximum total dose of 112,000 IU over a treatment period of up to 4 weeks. ENOXAPARIN SODIUM is utilized during the hospitalization phase of the study to provide prophylactic anticoagulation. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Following the initial treatment phase with ENOXAPARIN SODIUM, participants transition to oral anticoagulation therapy with **Eliquis**, which contains the active substance **APIXABAN**. Eliquis is provided in the form of **film-coated tablets**, with each tablet containing 2.5 mg of APIXABAN. The administration route is **oral**, with a dosing schedule of 2.5 mg taken twice daily, once in the morning and once in the evening. The maximum daily dose is 5 mg, and the total treatment period extends up to 12 weeks. The total maximum dose over the course of the study is 420 mg. Compliance with the oral dosing regimen is closely monitored to ensure accurate data collection and participant safety.

Both ENOXAPARIN SODIUM and Eliquis are integral components of the study, which aims to evaluate the efficacy of prolonged prophylactic anticoagulation in preventing venous thromboembolism in patients with warm-type autoantibody autoimmune hemolytic anemia. The trial does not include any non-experimental treatments such as placebo or comparator treatments, focusing solely on the efficacy of the anticoagulant regimen.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the prevention of venous thromboembolic events in patients with **autoimmune hemolytic anemia (AIHA)**. The primary endpoint is the occurrence of clinical venous thromboembolic events, specifically deep vein thrombosis (DVT) and pulmonary embolism (PE), within 24 weeks of randomization. These events will be confirmed through venous Doppler for DVT and thoracic CT angiography or ventilation/perfusion lung scintigraphy for PE.

Secondary endpoints include the time to onset of venous thromboembolic events within 24 weeks of AIHA diagnosis or relapse, and the occurrence of adverse events (AE) and serious adverse events (SAE). These include major hemorrhagic events, clinically significant non-major bleeding, minor bleeding, major cardiovascular events, splanchnic venous thrombosis, and death. Additionally, the study will determine biological factors that may contribute to or correlate with thromboembolic risk, such as D-dimer, sCD163, plasma hemoglobin, and NETose.

The efficacy parameters will be measured and collected at specified timepoints throughout the study duration, with the primary endpoint being assessed at 24 weeks. The analysis will involve validated diagnostic tools and imaging techniques to ensure accurate and reliable assessment of thromboembolic events and related outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient who provided free, written and informed consent
Patient aged ≥ 18 years
Patient with a diagnosis of primary or secondary autoimmune hemolytic anemia (AIHA) (infections, hematologic diseases, systemic diseases), according to the following criteria: - Hemoglobin <12 g/dL - and decreased haptoglobin (<0,4 g/L) - and positive direct antiglobulin test (direct Coombs test) (IgG +/- C3d)
Newly diagnosed or relapsed patient (relapse is defined as a decrease in basal hemoglobin in association with AIHA - thus meeting the above criteria: Hb <12 g/dl and haptoglobin <0.4 g/L and IgG-positive TDA with or without C3d - and for whom the investigator deems it necessary to initiate etiological treatment specific to AIHA)
Patient with an estimated life expectancy of more than 6 months

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Exclusion Criteria

Patients with immediate symptomatic VTE, confirmed by appropriate complementary examinations (venous Doppler of the lower limbs, thoracic CT angiography or pulmonary scintigraphy).
Patients on curative anticoagulation (VTE, atrial fibrillation)
Patient on dual antiplatelet treatment
Patient with active bleeding
Patient with a known condition or lesion at risk of bleeding
Patient with ischemic stroke with hemorrhagic transformation within 6 months prior to inclusion
Patient on preventive anticoagulation for 14 days or more
Patient with a contraindication to apixaban: - Known hypersensitivity to the molecule or to any of the excipients, - thrombocytopenia <100 G/L, - kidney failure (glomerular filtration rate < 30 ml/min/1.73m²), - Active liver disease (liver failure defined as Factor V <50% or INR >1.5, ALT elevation >2 times the upper limit of normal)
Patients receiving concomitant treatment with potent CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) or potent CYP3A4 inhibitors (azole antifungals, HIV protease inhibitors), if these treatments cannot be discontinued or modified.
Patients with a contraindication to enoxaparin: - hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low-molecular-weight heparins (LMWH), or to any of the excipients, - history of heparin-induced thrombocytopenia
Patient with cold agglutinin-related AIHA (C3d-positive ADT alone with identification of cold agglutinins)
Patient with severe hemostasis disorders: - hypofibrinogenemia < 2 g/L, - disseminated intravascular coagulation (APTT prolongation >1.2, and PT <50%, and thrombocytopenia <100 G/L, and D-Dimer >500 μg/L) - hemophilia
Patient whose clinical condition requires hospitalization in an intensive care unit
Patient who has already participated in the study
Patient not affiliated to national health insurance
Patient under legal protection (curatorship, guardianship)
Patient subject to a court order
Pregnant, parturient or breastfeeding women
Patient with physiological capacity to procreate (having had her first menstrual period and not menopausal and not presenting permanent sterility (hysterectomy, bilateral salpingectomy, bilateral oophorectomy)) and unable to have effective contraception (i.e., provided by an estrogenprogestin oral contraceptive or progestogen, a contraceptive implant, an intrauterine device or a tubal ligation)
Patient of legal age who is unable to provide consent